Abstract
In this study, we investigated antiparkinsonian activity of the novel, highly selective dopamine D2 receptor agonist sumanirole compared with two clinically effective dopaminergic therapies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. Squirrel monkeys were rendered parkinsonian by chronic administration of MPTP and subsequently dosed with vehicle, l-DOPA plus carbidopa (l-DOPA), ropinirole, or sumanirole over a duration of 8 weeks. Antiparkinsonian effects measured with a parkinsonian primate rating scale (PPRS) showed that sumanirole elicited improved functional outcome compared with vehicle. The dopamine D2/D3 agonist ropinirole improved behavioral outcome similar to sumanirole, whereas l-DOPA treatment yielded the most significant symptomatic improvement. The relative rank of therapies that elicited normalization of PPRS was l-DOPA > sumanirole; ropinirole did not normalize PPRS in any of the treated monkeys. Dyskinesias were present with l-DOPA treatment but were not observed in sumanirole-, ropinirole-, or placebo-treated primates. Pathologically, all MPTP-treated animals displayed neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and reactive astrocytosis. Neurons immunoreactive with antibodies to the nuclear transcription factor ΔFosB were most significantly increased in the striatum of l-DOPA-treated monkeys. These results suggest that sumanirole can exert antiparkinsonian effects similar to l-DOPA without the behavioral and morphological consequences of the latter.
Footnotes
-
This work was supported by Pfizer Global Research and Development. M.E.E. is partially supported by National Institutes of Health National Institute of Neurological Disorders and Stroke Grant R0I-NS40578 and National Institutes of Health Grant P51RR000167 to the Wisconsin National Primate Research Center, University of Wisconsin, Madison.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.105.087379.
-
ABBREVIATIONS: SN, substantia nigra; PD, Parkinson's disease; DA, dopamine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; ANOVA, analysis of variance; PPRS, primate parkinsonian rating scale; PBS, phosphate-buffered saline; CSF, cerebrospinal fluid; GFAP, glial fibrillary acidic protein; TH, tyrosine hydroxylase; DAB, diaminobenzidine; AUC, area under the plasma-concentration time curve; SNpc, substantia nigra pars compacta; ir, immunoreactivity; SS33084, (3aR, 9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c] pyrole-2-yl)-butyl]-(4-phenyl) benzamide.
- Received April 4, 2005.
- Accepted June 2, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|